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COMPOSITIONS UTILIZING ZSSZSZZQSZZ 21 155883 Ghesv-Lmihloup1 E A US008586621B2 (12) Ulllted States Patent (10) Patent N0.: US 8,586,621 B2 Zeligs (45) Date of Patent: Nov. 19, 2013 (54) ANTI-PARASITIC METHODS AND 2003/0211165 A1 11/2003 Vogel COMPOSITIONS UTILIZING ZSSZSZZQSZZ 21 155883 ghesv-lmihloup1 e a. DHNDOLYLMETHANE-RELATED INDOLES 2004/0022760 A1* 2/2004 McKenna et al. .......... .. 424/85.1 _ _ 2004/0142000 A1* 7/2004 Suga et al. ....... .. .. 424/195.15 (76) Inventor: MlchaelA- ZellgS, Boulder, CO (US) 2005/0158347 A1* 7/2005 Tarleton et al. 424/2691 2006/0100264 A1* 5/2006 Bjeldanes et al. .......... .. 514/414 ( * ) Notice: Subject to any disclaimer, the term of this 2006/0229355 A1 10/2006 Bjeldanes et al. patent is extended or adjusted under 35 Zoos/0145418 A1 6/2008 Zehgs et al' U.S.C. 154(b) by 257 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.1 12/447,307 EP 0566226 “V1993 _ W0 WO 96/30347 3/1996 (22) PCT Flledi Oct- 26, 2007 W0 WO 96/33980 10/1996 W0 WO 97/02266 1/1997 (86) PCT No.1 PCT/US2007/022649 W0 WO 97/30034 8/1997 W0 WO 97/38983 10/1997 § 371 (0X1), W0 W0 99/55683 11/1999 (2), (4) Date: Apr. 27, 2009 W0 W0 00/02857 1/2000 W0 WO 00/31048 6/2000 . W0 WO 01/20990 3/2001 (87) PCT Pub. No.. WO2008/057253 W0 W0 02/092575 110002 PCT pub Date; May 15, 2008 W0 WO 2004/071425 5/2004 W0 WO 2005/107747 11/2005 . W0 WO 2006/047716 5/2006 (65) Prior Publication Data W0 W0 2006/053l60 * 50006 US 2010/0055201A1 Mar. 4, 2010 OTHER PUBLICATIONS Related U.S.Application Data _ _ _ _ _ _ _ _ _ _ Rath et al. “Pharmacokmetrc study of Artemrsrnrn after oral rntake of (60) PrOVlslOnal apphcanon NO- 60/854,830, ?led on Oct atraditional preparation ofArtemisia annua L. (annual WormWood),” 27, 2006- Am. J. Trop. Med. Hyg. 2004 vol. 70, N0. 2, pp. 128-132.* 51 I Cl AggarWal & IchikaWa, 2005, “Molecular targets and anticancer ( ) nt' ' potential of indole-3-carbinol and its derivatives,” Cell Cycle A61K 31/40 (2006.01) 4(9):1201_15‘ A61K31/405 (200601) Akkar et al., 2003, “Formulation of intravenous carbamazepine emulsions by SolEmuls technology,” Eur J. Pharm Biopharm. ' 551305-12. A61K 9/00 (200601) Baugh et al., Jan. 23, 1998, “Treatment of cervical dysplasia With (52) U-s- Cl- indole-3-carbinol” in The Ray A. Barlow Scienti?c Symposium, USPC --------- ~- 514/415; 514/414; 514/420; 424/451; Shreveport : The Center for Excellence in Cancer Research, Treat 424/464; 424/400 ment and Education, Louisiana State University Medical Center, (58) Field of Classi?cation Search Shreveport (LA), p. 3. USPC ......... .. 514/414, 415, 420; 424/451, 464, 400 . See application ?le for complete search history. (Commued) (56) References Cited Primary Examiner * Shengjun Wang U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm * Jones Day 5,635,215 A 6/1997 Boschettiet al. 5,718,921 A 2/1998 MahtioWitZ etal. 5,830,887 A 11/1998 Kelly (57) ABSTRACT 5,895,787 A 4/1999 Arffmann et al. 5,948,808 A 9/1999 Safe The present invention includes methods and compositions for 6,086,915 A 7/2000 Zeligs et al. the treatment and prevention of protoZoal parasitic infections 6,399,645 B1 6/2002 Bell et al. utilizing Diindolylmethane-related indoles. Additive and 6,477,229 B1 11/2002 Grosser 6,534,085 B1* 3/2003 Zeligs ......................... .. 424/451 synergistic interaction of Diindolylmethane-related indoles 6,583,167 B2 6/2003 Palmer et al. With other knoWn anti-parasitic and pro-apoptotic agents is 6,613,792 B1 9/2003 Ellenberger et al. believed to permit more effective therapy and prevention of 6,656,963 B2 12/2003 Firestone et al. protoZoal parasitic infections. The methods and compositions 6,689,387 B1 2/2004 Zeligs 6,800,655 B2 10/2004 Jong et al. described provide neW treatment of protoZoal parasitic dis 7,348,352 B2 3/2008 Zeligs eases of mammals andbirds including malaria, leishmaniasis, 7,384,971 B2 6/2008 Zeligs trypanosomiasis, trichomoniasis, neosporosis and coccidi 7,384,972 B2 6/2008 Zeligs 7,709,520 B2 5/2010 Safe os1s. 7,989,486 B2 8/2011 Zeligs et al. 8,080,577 B2 12/2011 Zeligs et al. 2002/0147155 A1 10/2002 Fosteretal. 53 Claims, N0 Drawings US 8,586,621 B2 Page 2 (56) References Cited Hong et al., 2002, “Bc1-2 family-mediated apoptotic effects of 3,3‘ diindolylmethane (DIM) in human breast cancer cells,” Biochem OTHER PUBLICATIONS Pharmacol. 63:1085-97. Howard et al., 1989, “Intracerebral drug delivery in rats with lesion Bell et al., Mar. 1999, “Placebo-controlled Trial of Indole-3 -Carbinol induced memory de?cits,” J Neurosurg. 71 : 105-12. in the Treatment of Cervical Dysplasia”, Abstracts Presented for the Jin et al., 1999, “Indole-3 -carbinol prevents cervical cancer in human Thirtieth Annual Meeting of the Society of Gynecologic Oncologists papillomavirus type 16 (HPV 16) transgenic mice,” Cancer Res , Gynecol. Oncol. 72: 443-527 (Abstract 13). 59:3991-7. Bell et al., 2000, Placebo-Controlled Trial of Indole-3 -Carbinol in the Langer and Peppas, 1983, “Chemical and physical structure of Poly Treatment of CIN, Gynecologic Oncology 78: 123-129. mers as carriers sfor controlled release of bioactive agents: a review,” Bioresponse Letter, Dec. 29, 1998. J. Macromol Sci Rec Macromol. Chem. 23:61-126. Bioresponse-Dim Indolplex Product Information Brochure, Dec. 15, Langer et al., 1990, New methods of drug delivery, Science 1998. 249:1527-1533. Bj eldanes et al., 1991, “Aromatic hydrocarbon responsiveness-re Larsen- Su et al., 2001, “Transplacental expo sure to indole-3 -carbinol ceptor agonists generated from indole-3 -carbinol in vitro and in vivo: induces sex-speci?c expression of CYP1A1 and CYPlBl in the liver comparisons with 2,3,7,8,-tetrachlorodibenzo-p-dioxin,” Proc. Natl. of Fischer 344 neonatal rats,” Toxicological Sci. 64: 162-168. Acad. Sci. USA 88:9543-9547. Leong et al., 2004, “Potent ligand-independent estrogen receptor Bonnesen et al., 2001, “Dietary indoles and isothiocyanates that are activation by 3,3‘-diindolylmethane is mediated by cross talk generated from cruciferous vegetables can both induce apoptosis and between the protein kinase A and mitogen-activated protein kinase confer protection against DNA damage in human colon cell lines,” signaling pathways,” Mol Endocrinol. 18:291-302. Cancer Research, American Association for Cancer Research Liu et al., 1994, “Indolo[3,2-b]carbozole: a dietary-derived factor 61:6120-6130. that exhibits both antiestrogenic and estrogenic activity,” J. Natl. Brad?eld et al., 1987, “High-performance liquid chromatographic Cancer Inst. 86:1758-1765. Loria et al., 1990, “Immune response facilitation and resistance to analysis of anticarcinogenic indoles in Brassica oleracea,” J Agric virus and bacterial infectionis with dehydroepiandrosterone Food Chem 35:46-49. (DHEA),” Biologic Role of Dehydroepiandrosterone, pp. 107-130. Brad?eld et al., 1987, “Structure- Activity relationships of dietary Loub et al., 1975, “Aryl hydrocarbon hydroxylase induction in rat indoles: a proposed mechanism of action as modi?ers of xenobiotic tissues by naturally occurring indoles of cruciferous plants,” J. Natl. metabolism,” J Toxicol Environ Health 21:31 1-23. Cancer Inst. 54:985-988. Bradlow et al., 1999, “Multifunctional aspects of the action of indole Michnovicz et al., 1997, “Changes in levels of urinary estrogen 3-carbinol as an anti-tumor agent,” Annals of NewYork Academy of metabolites after oral indole-3 -carbinol treatment in humans”, J Natl Sciences 889: 204-213. Cancer Inst 89:718-23. Bradlow et al., 1996, “Z-hydroxyestrone: the ‘good’ estrogen,” J Mor?n R et al., 1994, “Pregnenolone and dehydroepiandrosterone as Endocrin 150:S259-S265. precursors of native 7-hydroxylated metabolites which increase the Brandi et al., 2003, “A new indole-3-carbinol tetrameric derivative immune response in mice,” J of Steroid Biochemistry and Molecular inhibits cyclin-dependent kinase 6 expression, and induces GI cell Biology, Elsevier Science Ltd., Oxford, GB, vol. 50(1/2) Jul. 1994, cycle arrest in both estrogen-dependent and estrogen-independent pp. 91-100. breast cancer cell lines,” Cancer Res. 63(14):4028-36. Muzandu et al., 2005, “Lycopene and beta-carotene ameliorate Calabro et al, 2005, “Inhibition of Tumor-Necrosis-Factor-or Induced catechol estrogen-mediated DNA damage,” Jpn J Vet Res. 52: 173-84. Endothelial Cell Activation by a New Class of PPAR-y: Agonists an Rahman et al., 2005, “Inhibition of Nuclear Translocation of Nuclear in vitro Study Showing Receptor-Independent Effects,” J Vasc Factor-kB Breast Cancer Cells Contributes to 3,3‘Diindolylmethane Induced Apoptosis in,” Cancer Res. 65:364-371. Res;42: 509-516. Riby et al., 2000, “Ligand-independent activation of estrogen recep Chang et al., 1999, “Cytostatic and antiestrogenic effects of tor function by 3,3‘-diindolylmethane in human breast cancer cells,” 2-(Indo1-3-ylmethyl)-3,3‘-diindolylmethane, a major in vivo product Biochem. Pharmacol. 60:167-177. of dietary indole-3 -carbinol,” Biochem. Pharmacol. 58:825-834. Ritter et al., 2001, “Oxidations of 17beta-estradiol and estrone and Chen et al., 1998, “Aryl hydrocarbon receptor-mediated their interconversions catalyzed by liver, mammary gland and mam antiestrogenic and antitumorigenic activity of dindoylmethane,” mary tumor after acute and chronic treatment of rats with indole-3 Carcinogenesis 19: 163 1-1639. carbinol or beta-naphtho?avine,” Can. J. Physiol. Pharmacol. Chen et al., 2001, “Indole-3-carbinol and diindolylmethane induce 79(6):519-32. apoptosis of human cervical cancer cells and in murine HPV16 Rogan, 2006, “The natural chemopreventive compound indole-3 transgenic preneoplastic cervical epithelium,” J Nutr.
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